Doctor Looks to Ashkenazim in Search for Schizophrenia Cure

Epidemiologist Ann Pulver found her research calling early. As an undergraduate at Boston University, she worked with schizophrenia patients and saw firsthand the devastation the disease can cause. She decided then to devote her career to fighting it.

Now, as head of the epidemiology-genetics program in psychiatry at Johns Hopkins University, Pulver is doing just that. She’s studying hundreds of Ashkenazic Jews with schizophrenia or bipolar disorder, and their families, to try to pin down the genetic roots of the two illnesses.

In an article in the December issue of the American Journal of Human Genetics, Pulver and her colleagues identified eight genes that may increase susceptibility to bipolar disorder and six associated with schizophrenia.

The findings may be particularly significant for Jews with the illnesses, as they could someday lead to early screening programs and better-targeted drug treatments.

Schizophrenia and bipolar disorder each affect about one out of 100 people. Researchers think that genetics may account for as much as 70% of a person’s likelihood of developing one of the illnesses. Unlike with a disease such as Tay-Sachs, however, researchers are not likely to discover a simple schizophrenia or bipolar-disorder gene. Instead, the illnesses are probably caused by a complex interaction of many different genes and environmental factors.

Schizophrenia and bipolar disorder are separate illnesses — people with bipolar disorder alternate between periods of depression and manic activity, and those with schizophrenia can suffer from delusions or hallucinations in addition to mood swings. But over the past several years, researchers have begun to suggest that the two illnesses may share some of the same genetic causes.

Pulver was one of the first to consider the possibility. Her early work focused mainly on schizophrenia. In the 1980s she began the first National Institute of Mental Health-funded research program on the genetics of schizophrenia.

“I was the first horse out of the gate in that,” she said.

In a 1998 genome-wide scan of schizophrenic patients and their relatives — non-Jews in this case — she found that family members with schizophrenia often shared particular sequences of DNA on chromosome 13, an area that had also been associated with susceptibility to bipolar disorder.

Pulver has continued her research with the general population, but in the late 1990s she began a second project, looking at the genes of Ashkenazic Jews. Schizophrenia and bipolar disorder are no more common in Jews than in any other population, Pulver said, but, because Ashkenazic Jews are more genetically homogenous than a random sample of the population, working with them makes it easier to spot the defective genes that could contribute to the illnesses. On her study’s Web site, Pulver likens her search to looking for a green M&M in a bowlful of the chocolates — it’s easier to spot it when all the other candies are red than when they include a rainbow of colors.

The downside to studying a limited population is that the genes that contribute to schizophrenia and bipolar disorder in Ashkenazic Jews may not be the same ones that lead to the illnesses for others. Most of the 14 genes identified in the December study, for example, are in different areas of the genome than the genes identified in general-population studies.

But the research is still valuable, Pulver and others in the field said, because identifying a gene that contributes to schizophrenia or bipolar disorder in any population can help researchers understand more about the physical causes of the disease.

“We know so little right now,” said Thomas Lehner, the acting director of the Office of Human Genetics and Genomic Resources at NIMH. “So if you can find a gene that explains even 5%, I’d go for it, because it might point to different pathways that would teach you about other populations.”

For the same reason, several researchers are studying schizophrenia and bipolar disorder in other genetically homogenous populations.

For these groups and others, Pulver said, the research may someday offer tangible benefits. Right now, doctors have a pharmaceutical cornucopia to offer patients who are diagnosed with the illnesses. But each person responds differently to each drug, and finding the best one for an individual can take years of trial and error.

“You try one, and if it doesn’t work you wait six months and try another,” Pulver said. “The process of finding the best medication with the least side effects is misery.”

Identifying specific genes that contribute to schizophrenia and bipolar disorder could help researchers parse different manifestations of the illnesses, which could then lead to an understanding of who responds best to what medications.

Though this type of knowledge may be a long way off, James Potash, a psychiatrist who also studies the genetics of mental-health disorders at John Hopkins, suggested that Pulver’s research may offer a second — and more immediate — benefit.

“I think that at one level merely identifying the variations in genes that make people susceptible to illness will go a long way towards destigmatizing the illnesses,” he said. “Because there are still lots and lots of people who think these illnesses are just defects of character or willpower.”

The five-year grant that funded Pulver’s reserach on Ashkenazic Jews is ending this year. She is in the process of applying for another federal grant. She’s also seeking funding from private sources, and hopes to establish a fund for Jewish genetic medicine. She recently received seed money from a philanthropist to begin a study of Ashkenazic Jews with Alzheimer’s disease. Some researchers think similar genes may link Alzheimer’s to schizophrenia.